Dw14(DRB1*0404) is a Dw4-dependent risk factor for rheumatoid arthritis. Rethinking the "shared epitope" hypothesis.

HLA-DR4 has been shown to be associated with risk for developing rheumatoid arthritis (RA) in multiple populations and racial groups. The allelic variants of DR4 share the DR4 serologic specificity but differ by 1 to 3 amino acids in the third hypervariable region (positions 67 to 74) and at positions 57 and 86 of the DR beta 1 chain. We have examined DR4 variants in 61 DR4+ RA cases and 55 DR4+ healthy controls. Dw14 was not associated with RA risk in DR4 heterozygous (DR4,X) cases. Only 15% of DR4,X cases had the Dw14 allele compared with 28% of DR4,X controls. In homozygous (DR4,4) individuals who also expressed Dw4, however, Dw14 was associated with increased RA risk. Moreover, the relative risk for Dw4,Dw14 (16.1, p = 0.001) actually exceeded that of Dw4,Dw4 (2.2, p = ns). Thus Dw14 is not an independent risk factor for RA but is a synergistic risk factor for individuals who also have the Dw4 allele.